PDE2 is a 105-KDa homodimer that is expressed in a wide variety of tissues and cell types including brain (including hippocampus, striatum and prefrontal cortex), heart, platelets, endothelial cells, adrenal glomerulosa cells and macrophages. Although cGMP is the preferred substrate and effector molecule for this enzyme, PDE2 hydrolyzes both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and is thought to be involved in a number of physiological processes. In particular, it has been shown that inhibition of nitric oxide synthase (NOS), which reduces cGMP signaling, attenuates the behavioral effects of the benzodiazepine chlordiazepoxide, an anxiolytic compound. Also, commercially-available tool inhibitors of PDE2 such as Bay 60-7550 have been shown to increase cyclic nucleotide levels in the brain and have significant anti-anxiety and anti-depressant effects in normal and stressed rodents (Xu et al., Eur. J. Pharmacol. (2005) 518:40-46; Masood et al., J. Pharmacol. Exp. Ther. (2008) 326:369-379; Masood et al., JPET (2009) 331:690-699; Xu et al., Intl. J. Neuropsychopharmacol. (2013) 16:835-847). Inhibition of PDE2 by Bay 60-7550 has also been shown to elevate cGMP and cAMP levels in stimulated primary neuronal cultures in a dose responsive manner; enhance LTP in hippocampal slice preparations in response to electrical stimulation; enhance learning in novel object recognition animal model and a social recognition task in rats; improve acquisition and consolidation phases of novel object memory in age impaired rats; improve performance on object location and recognition tasks when administered after training. Gomez et al., Bioorg. Med. Chem. Lett. (2013) 23:6522-6527. Bay 60-7550 has also been shown to improve cognition and memory function in rats through the enhancement of nNOS activity in the brain. (Domek-Lopacinska et al. (2008) Brain Res. 1216:68-77). Therefore, PDE2 plays an important role in effective behaviors and cognitive function.
In addition to effective behavior and cognitive function, it has been observed that in endothelial cells, PDE2A mRNA and activity are highly induced in response to tumor necrosis factor-α stimulation in vitro. Selective inhibition of PDE2 activity with 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one (PDP) greatly alters the barrier function of endothelial cells, suggesting that PDE2 is likely to play an important role in regulating fluid and protein integrity of the circulatory system under pathological conditions. Therefore, PDE2 may be a good pharmacological target for sepsis or in more localized inflammatory responses.
In a recent study, PDE2 inhibition has also been shown to elicit pulmonary dilation, prevents pulmonary vascular remodeling and reduces the right ventricular hypertrophy characteristic of pulmonary hypertension, suggesting therapeutic potential of PDE2 inhibition in pulmonary hypertension. Bubb et al., “Inhibition of Phosphodiesterase 2 Augments cGMP and cAMP Signaling to Ameliorate Pulmonary Hypertension”, Circulation, Aug. 5, 2014, p. 496-507, DOI:10.1161/CIRCULATIONAHA. 114.009751.
Despite the promising preclinical data and the identification of PDE2 as a promising drug target, no PDE2 inhibitors are currently known to be under clinical investigation due in part to the poor metabolic stability and brain penetrance of existing PDE2 compounds. There is thus a need for compounds that selectively inhibit PDE2 activity while demonstrate superior biophysical properties.